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Ischaemic stroke

Nature Reviews Disease Primers volume 5, Article number: 70 (2019) Cite this article

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Abstract

Stroke is the second highest cause of death globally and a leading cause of disability, with an increasing incidence in developing countries. Ischaemic stroke caused by arterial occlusion is responsible for the majority of strokes. Management focuses on rapid reperfusion with intravenous thrombolysis and endovascular thrombectomy, which both reduce disability but are time-critical. Accordingly, improving the system of care to reduce treatment delays is key to maximizing the benefits of reperfusion therapies. Intravenous thrombolysis reduces disability when administered within 4.5 h of the onset of stroke. Thrombolysis also benefits selected patients with evidence from perfusion imaging of salvageable brain tissue for up to 9 h and in patients who awake with stroke symptoms. Endovascular thrombectomy reduces disability in a broad group of patients with large vessel occlusion when performed within 6 h of stroke onset and in patients selected by perfusion imaging up to 24 h following stroke onset. Secondary prevention of ischaemic stroke shares many common elements with cardiovascular risk management in other fields, including blood pressure control, cholesterol management and antithrombotic medications. Other preventative interventions are tailored to the mechanism of stroke, such as anticoagulation for atrial fibrillation and carotid endarterectomy for severe symptomatic carotid artery stenosis.

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Fig. 1: Epidemiology of ischaemic stroke.
Fig. 2: Ischaemic stroke mechanisms.
Fig. 3: Cerebral vasculature.
Fig. 4: Cellular effects of ischaemia.
Fig. 5: Brain imaging to diagnose ischaemic stroke and identify salvageable brain tissue.

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References

  1. Sacco, R. L. et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44, 2064–2089 (2013).

    Article  PubMed  Google Scholar 

  2. Feigin, V. L. et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N. Engl. J. Med. 379, 2429–2437 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Astrup, J., Siesjo, B. K. & Symon, L. Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12, 723–725 (1981).

    Article  CAS  PubMed  Google Scholar 

  4. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587 (1995).

    Article  Google Scholar 

  5. Stroke Unit Trialists’ Collaboration. Collaborative systematic review of the randomised trials of organised inpatient (stroke unit) care after stroke. BMJ 314, 1151–1159 (1997). A key study demonstrating the benefits of care in a stroke unit for all stroke subtypes and subgroups.

    Article  Google Scholar 

  6. Emberson, J. et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384, 1929–1935 (2014). A meta-analysis of individual patient data from intravenous thrombolysis trials that emphasizes the important influence of time to treatment on patient outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thomalla, G. et al. MRI-guided thrombolysis for stroke with unknown time of onset. N. Engl. J. Med. 379, 611–622 (2018).

    Article  PubMed  Google Scholar 

  8. Ma, H. et al. A multicentre, randomized, double blinded, placebo controlled phase 3 study to investigate extending the time for thrombolysis in emergency neurological deficits (EXTEND). Int. J. Stroke 7, 74–80 (2012).

    Article  PubMed  Google Scholar 

  9. Campbell, B. C. V. et al. Extending thrombolysis to 4.5-9 hours and wake-up stroke using perfusion imaging: a meta-analysis of individual patient data from EXTEND, ECASS4-EXTEND and EPITHET. Lancet 394, 139–147 (2019). A meta-analysis of individual patient data from randomized controlled trials showing that extending thrombolysis to >4.5 h after onset is possible using brain perfusion imaging.

    Article  PubMed  Google Scholar 

  10. Goyal, M. et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387, 1723–1731 (2016). A meta-analysis of individual patient data from endovascular thrombectomy trials showing the robust benefits of therapy across the subgroups of age, clinical severity and occlusion location.

    Article  PubMed  Google Scholar 

  11. Albers, G. W. et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N. Engl. J. Med. 378, 708–718 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nogueira, R. G. et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N. Engl. J. Med. 378, 11–21 (2018). Together with reference 11, this study provides evidence that extending thrombectomy to >6 h after onset is possible using CT perfusion or MRI diffusion/perfusion imaging.

    Article  PubMed  Google Scholar 

  13. Saver, J. L. et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA 316, 1279–1288 (2016). A meta-analysis of individual patient data indicating the strong effect of time to treatment on patient outcome in endovascular thrombectomy trials.

    Article  PubMed  Google Scholar 

  14. Global Burden of Disease Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 439–458 (2019).

    Article  Google Scholar 

  15. World Stroke Organization. WSO global stroke fact sheet. WSO https://www.world-stroke.org/images/WSO_Global_Stroke_Fact_Sheet_final.pdf (2019).

  16. Global Burden of Disease Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study 2017. Lancet 392, 1736–1788 (2018).

    Article  Google Scholar 

  17. Feigin, V. L. et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: the GBD 2013 study. Neuroepidemiology 45, 161–176 (2015).

    Article  PubMed  Google Scholar 

  18. Krishnamurthi, R. V. et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the global burden of disease study 2010. Lancet Glob. Health 1, e259–e281 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Krishnamurthi, R. V. et al. Stroke prevalence, mortality and disability-adjusted life years in adults aged 20-64 years in 1990-2013: data from the global burden of disease 2013 study. Neuroepidemiology 45, 190–202 (2015).

    Article  PubMed  Google Scholar 

  20. Feigin, V. L., Norrving, B. & Mensah, G. A. Global burden of stroke. Circ. Res. 120, 439–448 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Bevan, S. et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genome-wide associations. Stroke 43, 3161–3167 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. O’Donnell, M. J. et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376, 112–123 (2010).

    Article  PubMed  Google Scholar 

  23. Bang, O. Y., Ovbiagele, B. & Kim, J. S. Nontraditional risk factors for ischemic stroke: an update. Stroke 46, 3571–3578 (2015).

    Article  PubMed  Google Scholar 

  24. Shah, A. S. et al. Short term exposure to air pollution and stroke: systematic review and meta-analysis. BMJ 350, h1295 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shaaban, A. M. & Duerinckx, A. J. Wall shear stress and early atherosclerosis: a review. AJR Am. J. Roentgenol. 174, 1657–1665 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, J. S., Kim, Y. J., Ahn, S. H. & Kim, B. J. Location of cerebral atherosclerosis: why is there a difference between East and West? Int. J. Stroke 13, 35–46 (2018).

    Article  PubMed  Google Scholar 

  27. Jia, B. et al. Mechanical thrombectomy and rescue therapy for intracranial large artery occlusion with underlying atherosclerosis. J. Neurointerv. Surg. 10, 746–750 (2018).

    Article  PubMed  Google Scholar 

  28. Holmstedt, C. A., Turan, T. N. & Chimowitz, M. I. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 12, 1106–1114 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hao, Y. et al. Predictors for symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke. Stroke 48, 1203–1209 (2017).

    Article  PubMed  Google Scholar 

  30. Nah, H. W., Kang, D. W., Kwon, S. U. & Kim, J. S. Diversity of single small subcortical infarctions according to infarct location and parent artery disease: analysis of indicators for small vessel disease and atherosclerosis. Stroke 41, 2822–2827 (2010).

    Article  PubMed  Google Scholar 

  31. Debette, S. et al. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nat. Genet. 47, 78–83 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Ducros, A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 11, 906–917 (2012).

    Article  PubMed  Google Scholar 

  33. Link, M. S. et al. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Circ. Arrhythm. Electrophysiol. 10, e004267 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Morillo, C. A., Banerjee, A., Perel, P., Wood, D. & Jouven, X. Atrial fibrillation: the current epidemic. J. Geriatr. Cardiol. 14, 195–203 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. Lau, D. H., Nattel, S., Kalman, J. M. & Sanders, P. Modifiable risk factors and atrial fibrillation. Circulation 136, 583–596 (2017).

    Article  PubMed  Google Scholar 

  36. Kirchhof, P. et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur. Heart J. 37, 2893–2962 (2016).

    Article  PubMed  Google Scholar 

  37. Hagen, P. T., Scholz, D. G. & Edwards, W. D. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin. Proc. 59, 17–20 (1984).

    Article  CAS  PubMed  Google Scholar 

  38. Mas, J. L. et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N. Engl. J. Med. 377, 1011–1021 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Saver, J. L. et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N. Engl. J. Med. 377, 1022–1032 (2017). A key randomized controlled trial demonstrating benefits of PFO closure in selected patients.

    Article  PubMed  Google Scholar 

  40. Sondergaard, L. et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N. Engl. J. Med. 377, 1033–1042 (2017).

    Article  PubMed  Google Scholar 

  41. Pruitt, A. A. Neurologic complications of infective endocarditis. Curr. Treat. Options Neurol. 15, 465–476 (2013).

    Article  PubMed  Google Scholar 

  42. Vaitkus, P. T. Left ventricular mural thrombus and the risk of embolic stroke after acute myocardial infarction. J. Cardiovasc. Risk 2, 103–106 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Grabowski, A., Kilian, J., Strank, C., Cieslinski, G. & Meyding-Lamade, U. Takotsubo cardiomyopathy — a rare cause of cardioembolic stroke. Cerebrovasc. Dis. 24, 146–148 (2007).

    Article  PubMed  Google Scholar 

  44. Arboix, A., Jimenez, C., Massons, J., Parra, O. & Besses, C. Hematological disorders: a commonly unrecognized cause of acute stroke. Expert Rev. Hematol. 9, 891–901 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Switzer, J. A., Hess, D. C., Nichols, F. T. & Adams, R. J. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 5, 501–512 (2006).

    Article  PubMed  Google Scholar 

  46. Zhang, H., Prabhakar, P., Sealock, R. & Faber, J. E. Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J. Cereb. Blood Flow Metab. 30, 923–934 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Campbell, B. C. V. et al. Failure of collateral blood flow is associated with infarct growth in ischemic stroke. J. Cereb. Blood Flow Metab. 33, 1168–1172 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rocha, M. & Jovin, T. G. Fast versus slow progressors of infarct growth in large vessel occlusion stroke: clinical and research implications. Stroke 48, 2621–2627 (2017).

    Article  PubMed  Google Scholar 

  49. Howells, D. W. et al. Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J. Cereb. Blood Flow Metab. 30, 1412–1431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. O’Collins, V. E. et al. 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467–477 (2006).

    Article  PubMed  CAS  Google Scholar 

  51. Obrenovitch, T. P. et al. Extracellular neuroactive amino acids in the rat striatum during ischaemia: comparison between penumbral conditions and ischaemia with sustained anoxic depolarisation. J. Neurochem. 61, 178–186 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984).

    Article  CAS  PubMed  Google Scholar 

  53. Wu, Q. J. & Tymianski, M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol. Brain 11, 15 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Mayer, M. L. & Miller, R. J. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons. Trends Pharmacol. Sci. 11, 254–260 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. Love, S. Oxidative stress in brain ischemia. Brain Pathol. 9, 119–131 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Zuo, M. et al. Wallerian degeneration in experimental focal cortical ischemia. Brain Res. Bull. 149, 194–202 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Bigourdan, A. et al. Early fiber number ratio is a surrogate of corticospinal tract integrity and predicts motor recovery after stroke. Stroke 47, 1053–1059 (2016).

    Article  PubMed  Google Scholar 

  58. Ozyurt, E., Graham, D. I., Woodruff, G. N. & McCulloch, J. Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat. J. Cereb. Blood Flow Metab. 8, 138–143 (1988).

    Article  CAS  PubMed  Google Scholar 

  59. Willmot, M., Gray, L., Gibson, C., Murphy, S. & Bath, P. M. A systematic review of nitric oxide donors and l-arginine in experimental stroke: effects on infarct size and cerebral blood flow. Nitric Oxide 12, 141–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Crumrine, R. C., Thomas, A. L. & Morgan, P. F. Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J. Cereb. Blood Flow Metab. 14, 887–891 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Hartings, J. A. et al. The continuum of spreading depolarizations in acute cortical lesion development: examining Leao’s legacy. J. Cereb. Blood Flow Metab. 37, 1571–1594 (2017).

    Article  PubMed  Google Scholar 

  62. Dohmen, C. et al. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann. Neurol. 63, 720–728 (2008).

    Article  PubMed  Google Scholar 

  63. Shen, P. P. et al. Cortical spreading depression-induced preconditioning in the brain. Neural Regen. Res. 11, 1857–1864 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rao, V. L., Bowen, K. K. & Dempsey, R. J. Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain. Neurochem. Res. 26, 497–502 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tarassishin, L., Suh, H. S. & Lee, S. C. LPS and IL-1 differentially activate mouse and human astrocytes: role of CD14. Glia 62, 999–1013 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Choudhury, G. R. & Ding, S. Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol. Dis. 85, 234–244 (2016).

    Article  PubMed  Google Scholar 

  68. Dewar, D., Underhill, S. M. & Goldberg, M. P. Oligodendrocytes and ischemic brain injury. J. Cereb. Blood Flow Metab. 23, 263–274 (2003).

    Article  PubMed  Google Scholar 

  69. Tanaka, K., Nogawa, S., Suzuki, S., Dembo, T. & Kosakai, A. Upregulation of oligodendrocyte progenitor cells associated with restoration of mature oligodendrocytes and myelination in peri-infarct area in the rat brain. Brain Res. 989, 172–179 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Hall, C. N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wojcik, C. & Di Napoli, M. Ubiquitin-proteasome system and proteasome inhibition: new strategies in stroke therapy. Stroke 35, 1506–1518 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Zhang, K. et al. The Pyk2/MCU pathway in the rat middle cerebral artery occlusion model of ischemic stroke. Neurosci. Res. 131, 52–62 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Bai, J. & Lyden, P. D. Revisiting cerebral postischemic reperfusion injury: new insights in understanding reperfusion failure, hemorrhage, and edema. Int. J. Stroke 10, 143–152 (2015).

    Article  PubMed  Google Scholar 

  74. Chamorro, A. et al. The immunology of acute stroke. Nat. Rev. Neurol. 8, 401–410 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Wimmer, I., Zrzavy, T. & Lassmann, H. Neuroinflammatory responses in experimental and human stroke lesions. J. Neuroimmunol. 323, 10–18 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Zrzavy, T. et al. Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts. Brain Pathol. 28, 791–805 (2018).

    Article  CAS  PubMed  Google Scholar 

  77. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Maysami, S. et al. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke. J. Cereb. Blood Flow Metab. 36, 596–605 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Elkins, J. et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 16, 217–226 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Llovera, G. et al. Results of a preclinical randomized controlled multicenter trial (pRCT): anti-CD49d treatment for acute brain ischemia. Sci. Transl Med. 7, 299ra121 (2015).

    Article  PubMed  CAS  Google Scholar 

  81. Cushing, H. I. On the avoidance of shock in major amputations by cocainization of large nerve-trunks preliminary to their division, with observations on blood-pressure changes in surgical cases. Ann. Surg. 36, 321–345 (1902).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ko, N. U. in Aminoff’s Neurology and General Medicine (ed. Aminoff, M. J.) 183–198 (Academic Press, 2014).

  83. Shanahan, W. Acute pulmonary edema as a complication of epileptic seizures. NY Med. J. 16, 54–56 (1908).

    Google Scholar 

  84. L’E Orme, R. M., McGrath, N. M., Rankin, R. J. & Frith, R. W. Extracranial vertebral artery dissection presenting as neurogenic pulmonary oedema. Aust. NZ J. Med. 29, 824–825 (1999).

    Article  Google Scholar 

  85. Anrather, J. & Iadecola, C. Inflammation and stroke: an overview. Neurotherapeutics 13, 661–670 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zi, W. J. & Shuai, J. Cortisol as a prognostic marker of short-term outcome in Chinese patients with acute ischemic stroke. PLOS ONE 8, e72758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Offner, H. et al. Experimental stroke induces massive, rapid activation of the peripheral immune system. J. Cereb. Blood Flow Metab. 26, 654–665 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Courties, G. et al. Ischemic stroke activates hematopoietic bone marrow stem cells. Circ. Res. 116, 407–417 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Crapser, J. et al. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. Aging 8, 1049–1063 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Singh, V. et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J. Neurosci. 36, 7428–7440 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wu, S., Mead, G., Macleod, M. & Chalder, T. Model of understanding fatigue after stroke. Stroke 46, 893–898 (2015).

    Article  PubMed  Google Scholar 

  92. Desowska, A. & Turner, D. L. Dynamics of brain connectivity after stroke. Rev. Neurosci. 30, 605–623 (2019).

    Article  PubMed  Google Scholar 

  93. Jin, K. et al. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl Acad. Sci. USA 103, 13198–13202 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lees, J. S. et al. Stem cell-based therapy for experimental stroke: a systematic review and meta-analysis. Int. J. Stroke 7, 582–588 (2012).

    Article  PubMed  Google Scholar 

  95. Zheng, H. et al. Mesenchymal stem cell therapy in stroke: a systematic review of literature in pre-clinical and clinical research. Cell Transpl. 27, 1723–1730 (2018).

    Article  Google Scholar 

  96. Huang, H. et al. Intraparenchymal neural stem/progenitor cell transplantation for ischemic stroke animals: a meta-analysis and systematic review. Stem Cells Int. 2018, 4826407 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. Bal, S. et al. Time dependence of reliability of noncontrast computed tomography in comparison to computed tomography angiography source image in acute ischemic stroke. Int. J. Stroke 10, 55–60 (2015).

    Article  PubMed  Google Scholar 

  98. Roman, L. S. et al. Imaging features and safety and efficacy of endovascular stroke treatment: a meta-analysis of individual patient-level data. Lancet Neurol. 17, 895–904 (2018).

    Article  PubMed  Google Scholar 

  99. Hjort, N. et al. Ischemic injury detected by diffusion imaging 11 minutes after stroke. Ann. Neurol. 58, 462–465 (2005).

    Article  PubMed  Google Scholar 

  100. Campbell, B. C. V. et al. The infarct core is well represented by the acute diffusion lesion: sustained reversal is infrequent. J. Cereb. Blood Flow Metab. 32, 50–56 (2012).

    Article  PubMed  Google Scholar 

  101. Simard, J. M., Kent, T. A., Chen, M., Tarasov, K. V. & Gerzanich, V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 6, 258–268 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Colchero, M. A., Rivera-Dommarco, J., Popkin, B. M. & Ng, S. W. In Mexico, evidence of sustained consumer response two years after implementing a sugar-sweetened beverage tax. Health Aff. 36, 564–571 (2017).

    Article  Google Scholar 

  103. Castellano, J. M. et al. A polypill strategy to improve adherence: results from the FOCUS project. J. Am. Coll. Cardiol. 64, 2071–2082 (2014).

    Article  PubMed  Google Scholar 

  104. McNeil, J. J. et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N. Engl. J. Med. 379, 1509–1518 (2018). A key randomized controlled trial demonstrating a lack of benefit of aspirin in patients without established cardiovascular disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Freedman, B., Potpara, T. S. & Lip, G. Y. Stroke prevention in atrial fibrillation. Lancet 388, 806–817 (2016).

    Article  PubMed  Google Scholar 

  106. Lindsay, P., Furie, K. L., Davis, S. M., Donnan, G. A. & Norrving, B. World Stroke Organization global stroke services guidelines and action plan. Int. J. Stroke 9, 4–13 (2014).

    Article  PubMed  Google Scholar 

  107. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 349, 1641–1649 (1997).

    Article  Google Scholar 

  108. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 349, 1569–1581 (1997).

    Article  Google Scholar 

  109. Sacco, R. L. et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N. Engl. J. Med. 359, 1238–1251 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Johnston, S. C. et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N. Engl. J. Med. 379, 215–225 (2018). A key randomized controlled trial demonstrating the benefits of aspirin and clopidogrel for ~3 weeks in patients with minor stroke and TIA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Johnston, S. C. et al. Time course for benefit and risk of clopidogrel and aspirin after acute transient ischemic attack and minor ischemic stroke. Circulation 140, 658–664 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Hacke, W. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 274, 1017–1025 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Hacke, W. et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 352, 1245–1251 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Albers, G. W., Clark, W. M., Madden, K. P. & Hamilton, S. A. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. Stroke 33, 493–495 (2002).

    Article  PubMed  Google Scholar 

  115. Clark, W. M. et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The Atlantis study: a randomized controlled trial. alteplase thrombolysis for acute noninterventional therapy in ischemic stroke. JAMA 282, 2019–2026 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Sandercock, P. et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet 379, 2352–2363 (2012).

    Article  PubMed  CAS  Google Scholar 

  117. Lees, K. R. et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375, 1695–1703 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Muchada, M. et al. Impact of time to treatment on tissue-type plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 45, 2734–2738 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Logallo, N. et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 16, 781–788 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Mair, G. et al. Arterial obstruction on computed tomographic or magnetic resonance angiography and response to intravenous thrombolytics in ischemic stroke. Stroke 48, 353–360 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Barow, E. et al. Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the wake-up trial. JAMA Neurol. 76, 641–649 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Stroke Foundation. National stroke audit acute services. InformMe https://informme.org.au/stroke-data/Acute-audits (2017).

  123. Tanswell, P., Modi, N., Combs, D. & Danays, T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin. Pharmacokinet. 41, 1229–1245 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. O’Gara, P. T. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 127, e362–e425 (2013).

    Article  PubMed  Google Scholar 

  125. Coutts, S. B., Berge, E., Campbell, B. C., Muir, K. W. & Parsons, M. W. Tenecteplase for the treatment of acute ischemic stroke: a review of completed and ongoing randomized controlled trials. Int. J. Stroke 13, 885–892 (2018).

    Article  PubMed  Google Scholar 

  126. Parsons, M. W. et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N. Engl. J. Med. 366, 1099–1107 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Campbell, B. C. V. et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N. Engl. J. Med. 378, 1573–1582 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Bivard, A. et al. Tenecteplase in ischemic stroke offers improved recanalization: analysis of 2 trials. Neurology 89, 62–67 (2017).

    Article  PubMed  Google Scholar 

  129. Powers, W. J. et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 49, e46–e110 (2018).

    Article  PubMed  Google Scholar 

  130. Whiteley, W. N. et al. Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet Neurol. 15, 925–933 (2016).

    Article  PubMed  Google Scholar 

  131. Chia, N. H., Leyden, J. M., Newbury, J., Jannes, J. & Kleinig, T. J. Determining the number of ischemic strokes potentially eligible for endovascular thrombectomy: a population-based study. Stroke 47, 1377–1380 (2016).

    Article  PubMed  Google Scholar 

  132. Campbell, B. C. V. et al. Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data. Lancet Neurol. 17, 47–53 (2018).

    Article  PubMed  Google Scholar 

  133. Broderick, J. P. et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 368, 893–903 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lapergue, B. et al. Effect of endovascular contact aspiration vs stent retriever on revascularization in patients with acute ischemic stroke and large vessel occlusion: the ASTER randomized clinical trial. JAMA 318, 443–452 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Turk, A. S., Siddiqui, A. H. & Mocco, J. A comparison of direct aspiration versus stent retriever as a first approach (‘COMPASS’): protocol. J. Neurointerv. Surg. 10, 953–957 (2018).

    Article  PubMed  Google Scholar 

  136. Liu, X. et al. Acute basilar artery occlusion: endovascular interventions versus standard medical treatment (best) trial-design and protocol for a randomized, controlled, multicenter study. Int. J. Stroke 12, 779–785 (2017).

    Article  PubMed  Google Scholar 

  137. Ng, F. C. et al. Deconstruction of interhospital transfer workflow in large vessel occlusion: real-world data in the thrombectomy era. Stroke 48, 1976–1979 (2017).

    Article  PubMed  Google Scholar 

  138. Menon, B. K. et al. Association of clinical, imaging, and thrombus characteristics with recanalization of visible intracranial occlusion in patients with acute ischemic stroke. JAMA 320, 1017–1026 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Perez de la Ossa, N. et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 45, 87–91 (2014).

    Article  PubMed  Google Scholar 

  140. Llanes, J. N. et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp. Emerg. Care 8, 46–50 (2004).

    Article  PubMed  Google Scholar 

  141. Zhao, H. et al. Ambulance clinical triage for acute stroke treatment: paramedic triage algorithm for large vessel occlusion. Stroke 49, 945–951 (2018).

    Article  PubMed  Google Scholar 

  142. Ebinger, M. et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 311, 1622–1631 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Ehlers, L., Muskens, W. M., Jensen, L. G., Kjolby, M. & Andersen, G. National use of thrombolysis with alteplase for acute ischaemic stroke via telemedicine in Denmark: a model of budgetary impact and cost effectiveness. CNS Drugs 22, 73–81 (2008).

    Article  PubMed  Google Scholar 

  144. Shireman, T. I. et al. Cost-effectiveness of solitaire stent retriever thrombectomy for acute ischemic stroke: results from the swift-prime trial (solitaire with the intention for thrombectomy as primary endovascular treatment for acute ischemic stroke). Stroke 48, 379–387 (2017).

    Article  PubMed  Google Scholar 

  145. World Health Organization. World Health Organization model list of essential medicines, 21st list https://apps.who.int/iris/bitstream/handle/10665/325771/WHO-MVP-EMP-IAU-2019.06-eng.pdf?ua=1 (2019).

  146. World Bank. World Bank national accounts data https://data.worldbank.org/country/india (2017).

  147. Anderson, C. S. et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N. Engl. J. Med. 374, 2313–2323 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Vahedi, K. et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 6, 215–222 (2007).

    Article  PubMed  Google Scholar 

  149. Sheth, K. N. et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 15, 1160–1169 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Sherman, D. G. et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 369, 1347–1355 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. CLOTS Trial Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 382, 516–524 (2013).

    Article  Google Scholar 

  152. Middleton, S. et al. Implementation of evidence-based treatment protocols to manage fever, hyperglycaemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial. Lancet 378, 1699–1706 (2011).

    Article  PubMed  Google Scholar 

  153. Anderson, C. S. et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. Lancet 393, 877–888 (2019).

    Article  PubMed  Google Scholar 

  154. RIGHT Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet 393, 1009–1020 (2019).

    Article  Google Scholar 

  155. Sandset, E. C. et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet 377, 741–750 (2011).

    Article  CAS  PubMed  Google Scholar 

  156. Arima, H. et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J. Hypertens. 24, 1201–1208 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 373, 2103–2116 (2015).

    Article  CAS  Google Scholar 

  158. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348, 1329–1339 (1996).

    Article  Google Scholar 

  159. Wang, Y. et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N. Engl. J. Med. 369, 11–19 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Giannandrea, D. et al. Intravenous thrombolysis in stroke after dabigatran reversal with idarucizumab: case series and systematic review. J. Neurol. Neurosurg. Psychiatry 90, 619–623 (2019).

    Article  PubMed  Google Scholar 

  161. Zhao, H. et al. Prehospital idarucizumab prior to intravenous thrombolysis in a mobile stroke unit. Int. J. Stroke 14, 265–269 (2019).

    Article  PubMed  Google Scholar 

  162. Nishimura, M., Sab, S., Reeves, R. R. & Hsu, J. C. Percutaneous left atrial appendage occlusion in atrial fibrillation patients with a contraindication to oral anticoagulation: a focused review. Europace 20, 1412–1419 (2017).

    Article  Google Scholar 

  163. Amarenco, P. et al. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355, 549–559 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Sabatine, M. S., Giugliano, R. P. & Pedersen, T. R. Evolocumab in patients with cardiovascular disease. N. Engl. J. Med. 377, 787–788 (2017).

    PubMed  Google Scholar 

  165. Halliday, A. et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 376, 1074–1084 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Howard, G. et al. Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials. Lancet 387, 1305–1311 (2016).

    Article  PubMed  Google Scholar 

  167. Chimowitz, M. I. et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N. Engl. J. Med. 365, 993–1003 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Lechat, P. et al. Prevalence of patent foramen ovale in patients with stroke. N. Engl. J. Med. 318, 1148–1152 (1988).

    Article  CAS  PubMed  Google Scholar 

  169. AVERT Trial Collaboration Group. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet 386, 46–55 (2015).

    Article  Google Scholar 

  170. Stroke Foundation. Clinical guidelines for stroke management 2017. InformMe https://informme.org.au/Guidelines (2017).

  171. ATTEND Collaborative Group. Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial. Lancet 390, 588–599 (2017).

    Article  Google Scholar 

  172. Chaisinanunkul, N. et al. Adopting a patient-centered approach to primary outcome analysis of acute stroke trials using a utility-weighted modified Rankin scale. Stroke 46, 2238–2243 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Ragoschke-Schumm, A. et al. Retrospective consent to hemicraniectomy after malignant stroke among the elderly, despite impaired functional outcome. Cerebrovasc. Dis. 40, 286–292 (2015).

    Article  PubMed  Google Scholar 

  174. Lam, K. H. & Kwa, V. I. H. Validity of the PROMIS-10 Global Health assessed by telephone and on paper in minor stroke and transient ischaemic attack in the Netherlands. BMJ Open 8, e019919 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Cella, D. et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology. Neurology 78, 1860–1867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Golicki, D. et al. Validity of EQ-5D-5L in stroke. Qual. Life Res. 24, 845–850 (2015).

    Article  PubMed  Google Scholar 

  177. Lansberg, M. G. et al. Computed tomographic perfusion to predict response to recanalization in ischemic stroke. Ann. Neurol. 81, 849–856 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Lansberg, M. G. et al. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol. 11, 860–867 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Liebeskind, D. S. et al. eTICI reperfusion: defining success in endovascular stroke therapy. J. Neurointerv. Surg. 11, 433–438 (2018).

    Article  PubMed  Google Scholar 

  180. Miteff, F. et al. The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke. Brain 132, 2231–2238 (2009).

    Article  PubMed  Google Scholar 

  181. Bladin, C. et al. Magnetically-enhanced diffusion (MED™) of intravenous tPA in acute ischemic stroke: a pilot safety and feasibility trial. Stroke 46, A187 (2015).

    Google Scholar 

  182. Martinod, K. & Wagner, D. D. Thrombosis: tangled up in NETs. Blood 123, 2768–2776 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cook, D. J., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012).

    Article  CAS  PubMed  Google Scholar 

  184. Hill, M. D. et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 11, 942–950 (2012).

    Article  CAS  PubMed  Google Scholar 

  185. van der Worp, H. B. et al. EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. Int. J. Stroke 9, 642–645 (2014).

    Article  PubMed  Google Scholar 

  186. Shuaib, A. et al. Partial aortic occlusion for cerebral perfusion augmentation: safety and efficacy of NeuroFlo in Acute Ischemic Stroke trial. Stroke 42, 1680–1690 (2011).

    Article  PubMed  Google Scholar 

  187. Anderson, C. S. et al. Cluster-randomized, crossover trial of head positioning in acute stroke. N. Engl. J. Med. 376, 2437–2447 (2017).

    Article  PubMed  Google Scholar 

  188. Levi, H. et al. Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model. PLOS ONE 7, e39636 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bornstein, N. M. et al. An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial. Lancet 394, 219–229 (2019).

    Article  CAS  PubMed  Google Scholar 

  190. Meretoja, A. et al. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology 79, 306–313 (2012).

    Article  PubMed  Google Scholar 

  191. Meretoja, A. et al. Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months. Neurology 81, 1071–1076 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Feigin, V. L. et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 15, 913–924 (2016).

    Article  PubMed  Google Scholar 

  193. Strong, K., Mathers, C. & Bonita, R. Preventing stroke: saving lives around the world. Lancet Neurol. 6, 182–187 (2007).

    Article  PubMed  Google Scholar 

  194. Rodgers, H. et al. Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial. Lancet 394, 51–62 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10, 123–130 (2011).

    Article  CAS  PubMed  Google Scholar 

  196. Steinberg, G. K. et al. Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study. J. Neurosurg. 1, 1–11 (2018).

    Article  Google Scholar 

  197. Savoiardo, M. The vascular territories of the carotid and vertebrobasilar systems. Diagrams based on CT studies of infarcts. Ital. J. Neurol. Sci. 7, 405–409 (1986).

    Article  CAS  PubMed  Google Scholar 

  198. George, P. M. & Steinberg, G. K. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87, 297–309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia

    Bruce C. V. Campbell, Stephen M. Davis & Geoffrey A. Donnan

  2. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

    Bruce C. V. Campbell & Geoffrey A. Donnan

  3. Department of Neurology, Singapore General Hospital campus, National Neuroscience Institute, Singapore, Singapore

    Deidre A. De Silva

  4. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    Malcolm R. Macleod

  5. Departments of Clinical Neurosciences, Radiology and Community Health Sciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

    Shelagh B. Coutts

  6. Department of Neurology and Comprehensive Stroke Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Lee H. Schwamm

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Campbell, B.C.V., De Silva, D.A., Macleod, M.R. et al. Ischaemic stroke. Nat Rev Dis Primers 5, 70 (2019). https://doi.org/10.1038/s41572-019-0118-8

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